2.1. TARGETED AND LOCALIZED DRUG DELIVERY SYSTEMS
In order to exert characteristic therapeutic effects an administered drug must reach the proper site of action at an appropriate concentration. Thus, desirable features of drug delivery systems include resistance to rapid clearance and sustained release of drug at its site of activity. Another desirable feature is the ability to deliver the drug to a specific site of intended action without adversely affecting non-target tissues or systems. This latter feature is especially important when administering drugs such as anti-tumor agents which are particularly toxic, or drugs such as local anesthetics or steroid hormones which may have undesirable systemic side effects.
Although much has been written regarding the potential advantages of lipid vesicles or liposomes as in vivo drug delivery systems, failure to deliver drug to a specific site of activity continues to be a serious drawback (see review by Mayhew and Papahadjopoulos, 1983, "Therapeutic Applications of Liposomes" in Liposomes, Ostro, ed., Marcel Dekker, Inc., pp. 289-341).
Administration of targeted liposome preparations (liposomes designed to "home" to specific tissue or cell sites upon application in vivo) has been attempted by a number of researchers. Liposomes bearing substances such as antigenic lipids, i.e., N-dinitrophenyl-aminocaproyl phosphatidylethanolamine (Lesserman et al., 1979, J. Immunol. 122: 585-591), heat-aggregated IgM molecules (Weissman et al., 1975, Proc. Natl. Acad. Sci. U.S.A. 72: 88-92) , and sialoglycoprotein which binds lectins (Juliano and Stamp, 1976, Nature (London) 261:235-238)) have been used in vitro to enhance specific binding to cell surfaces. Huang et al., 1980, J. Bill. Chem. 255:8015-8018, demonstrated specific binding of liposomes to mouse L-929 cells in vitro by incorporation of anti-H-2-monoclonal antibody linked to palmitic acid into the lipid bilayer. More recently, Martin and Papahadjopoulos have demonstrated targeting of liposome preparations by the covalent linkage of Fab' fragments via disulfide bonds to a derivative of phosphatidylethanolamine incorporated into the lipid bilayer (1982, J. Biol. Chem. 257:286-288; Martin, Hubbell and Papahadjopoulos, 1981, Biochem. 20:4229-4238).
The use of of liposome preparations for localized drug delivery has also been attempted. In the liposome preparations which are designed to adhere at the site of administration, enhanced affinity is conferred by means of "stick" adjuvants. Liposomes with synthetic amino-saccharide compounds conjugated to cholesterol incorporated into the lipid bilayer have been shown to have enhanced affinity for cells or tissues when extravascularly applied by subcutaneous administration (Wu et al., 1981, Biochim. Biophys. Acta 674:19-29; Wu et al., 1981, Proc. Natl. Acad. Sci., U.S.A. 78:2033-2037).
Localized drug delivery has also been attempted by utilization of specific routes of administration. For example localized administration of steroid (cortisol palmirate) entrapped in dipalmitoylphosphatidylcholine liposomes by means of intra-articular administration to joints has been demonstrated to have superior anti-inflammatory activity compared to administration of free steroid (Shaw et al., 1978, Ann. N.Y. Acad. Sci. 308: 435-436; Philips et al., 1979, Ann. Rheum. Dis. 38: 553-557).